PROJECT SUMMARY Cognitive impairment, defined by reduced attention, diminished learning and memory, and impaired reasoning, is a common and pressing public health concern, afflicting 16 million Americans and increasing globally (CDC 2011). Aging constitutes the greatest risk factor for cognitive impairment, and the American aging population is expected to increase to 88.5 million people by 2050. There is a pressing public health need to identify clinically tractable targets for prevention and/or treatment of cognitive impairment arising from both the lack of current treatment options and the rising aging population. Environmental factors including hypoxic insult and dietary consumption contribute to cognitive impairment probability, but precise mechanisms for how environmental factors interact with impairment risk remains poorly understood. The gut microbiota mediates environmental contributions to host health and disease and causally modulates cognitive behavior in the novel object recognition, Barnes maze, and Morris water maze tasks. Together, this evidence warrants investigation into whether the gut microbiota modulates cognition during adulthood and aging. Our preliminary data support our central hypothesis that the gut microbiota is important for mediating detrimental effects of hypoxia (Hyp) murine hippocampal-dependent cognitive performance under ketogenic diet (KD) consumption. Given the similarities between molecular mechanisms for Hyp-induced and aging-induced cognitive impairment, we further hypothesize that select microbes modify aging-induced cognitive deficits. Our rationale is that identification of gut microbes contributing to cognition through changes in hippocampal and/or vagal nerve signaling pathways will offer new therapeutic opportunities for aging-induced cognitive impairment. Our specific aims test the following hypotheses: Aim 1: Identify specific microbial taxa that mediate effects of the ketogenic diet (KD) and hypoxia (Hyp) on cognitive behavior and test whether treatment with select microbes modifies cognitive deficits due to aging; Aim 2: Determine roles for the gut microbiota in modulating hippocampal activity relevant to cognitive behavior; Aim 3: Assess the contribution of vagal nerve signaling to microbiota- dependent modulation of cognitive behavior. Upon conclusion, we will gain better understanding of how the gut microbiota modulates cognitive behavioral outcomes. This contribution is significant since it represents a mechanistic approach towards identifying microbiota manipulations that could serve as clinically tractable therapeutic targets to aid cognition. Future studies will analyze the role microbiota-gut-brain circuits play in microbial modulation of host cognition and focus on identifying precise microbial molecules responsible for cognitive behavioral changes.